Three million phenytoin-treated epileptic Americans manifest some degree of gingival overgrowth. In these lesions, an increase in the dimension of the connective tissue component of the gingivae is always observed, yet the pathogenesis of the condition has remained largely unknown. Recent data from our laboratory using a feline model indicate that a phenytoin metabolite and not the parent drug is a primary etiologic factor. Furthermore, from our in vitro cell culture studies, we have determined that the most likely mechanism of action is one of in vivo selection of a phenotypically stable subpopulation of fibroblasts characterized by elevated protein and collagen synthetic activities. The broad aim of the proposed studies is to elucidate further the roles of host drug metabolism and fibroblast subpopulation selection in the pathogenesis of phenytoin-induced gingival overgrowth. By breeding a colony of known responder and non-responder cats, we shall be able to ascertain the possible role of host genetics in drug metabolism and clearance, as well as determine the comparability of the feline model lesion to that in humans. Further in vitro studies of the phenotypically bizarre human gingival fibroblast derived from enlarged gingivae will reveal whether or not there is any direct cytotoxic or mitogenic action of phenytoin or a metabolite on cells. The mechanism of drug-cell interaction will be pursued in vitro, as will the possiblity of focal drug metabolism by fibroblasts. The transmission electron microscope will be used to ascertain any morphological peculiarities in cultured fibroblasts, and to study the ultrastructural features of overgrown gingival tissue. Knowledge gained from the proposed experiments may provide the rationale for development of new prophylactic and/or therapeutic approaches in the control of gingival overgrowth as well as other similar-appearing and clinically more significant fibrotic-hyperplastic connective tissue lesions such as burn scar, keloid, arthritic joints, scleroderma and systemic lupus erythematosis.